lewis-x-antigen and Skin-Neoplasms

Cutaneous T cell lymphomas (CTCL) are rare and histologically diverse lymphoproliferative neoplasms, with mycosis fungoides (MF) representing the most common disease subset. Given the emerging role of myeloid-derived suppressor cells (MDSC) as a clinically applicable biomarker in solid tumors, we sought to investigate the presence of tumor-infiltrating and circulating MDSC in early- and advanced-stage MF patients and evaluate their prognostic significance in patient overall survival.. Tumor-infiltrating MDSC were assessed immunohistochemically with Arginase-1 in 31 MF and 14 non-MF skin punch biopsies. Circulating MDSC were assessed with flow cytometry in freshly isolated PBMC from 29 MF patients. Granulocytic MDSC (G-MDSC) were defined as CD11b+CD14-CD15+ and monocytic MDSC (M-MDSC) were defined as CD11b+CD14+HLA-DRlow/-.. MDSC infiltration occurred in approximately one-third (35.5%) of CTCL lesions, with a predilection for non-MF lesions (p < 0.05). The predominant morphology of MDSC was granulocytic. Although in MF lesions the presence of MDSC infiltrates did not correlate with clinical stage, it conferred significantly worse overall survival outcomes (p < 0.05). Circulating G-MDSC were significantly higher in MF patients compared to healthy donor controls (p < 0.0001), while M-MDSC did not show any statistically significant difference. G-MDSC were significantly higher in patients with active disease compared to patients who were in partial remission (p < 0.01). As with tumor-infiltrating MDSC, clinical stage did not correlate with circulating G-MDSC levels, while prospective overall survival analysis showed that patients with high levels of circulating G-MDSC have significantly inferior outcomes (p < 0.01).. This study shows that G-MDSC could represent a novel and easily assessable biomarker in MF, which mirrors disease activity and can predict patient subgroups with aggressive clinical features.

Topics: CD11b Antigen; Cell Count; Female; Flow Cytometry; Granulocytes; HLA-DR Antigens; Humans; Immunohistochemistry; Lewis X Antigen; Lipopolysaccharide Receptors; Male; Monocytes; Mycosis Fungoides; Myeloid-Derived Suppressor Cells; Neoplasm Staging; Prognosis; Skin Neoplasms; Survival Rate

Malignant melanoma is a destructive and lethal form of skin cancer with poor prognosis. An effective treatment for melanoma is greatly needed. Ginsenoside Rg3 is a herbal medicine with high antitumor activity. It is reported that abnormal glycosylation is correlated with the tumor cell growth. However, the antitumor effect of Rg3 on melanoma and its mechanism on regulating glycosylation are unknown. We found that Rg3 did not only inhibit A375 melanoma cell proliferation in a dose-dependent manner, but also decreased the expression of fucosyltransferase IV (FUT4) and its synthetic product Lewis Y (LeY), a tumor-associated carbohydrate antigen (TACA). Knocking down FUT4 expression by siRNA dramatically reduced FUT4/LeY level and inhibited cell proliferation through preventing the activation of EGFR/MAPK pathway. Consistently, the inhibitory effect of the Rg3 and FUT4 knockdown on melanoma growth was also seen in a xenograft melanoma mouse model. In conclusion, Rg3 effectively inhibited melanoma cell growth by downregulating FUT4 both in vitro and in vivo. Targeting FUT4/LeY mediated fucosylation by Rg3 inhibited the activation of EGFR/MAPK pathway and prevented melanoma growth. Results from this study suggest Rg3 is a potential novel therapy agent for melanoma treatment.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; Fucosyltransferases; Ginsenosides; Humans; Lewis Blood Group Antigens; Lewis X Antigen; Male; MAP Kinase Signaling System; Melanoma; Mice; Mice, Nude; Skin Neoplasms; Xenograft Model Antitumor Assays

Abnormal glycosylation is catalyzed by the specific glycosyltransferases and correlates with tumor cell apoptosis. Increased fucosyltransferase IV (FUT4) is seen in many types of cancer, and manipulating FUT4 expression through specific signaling pathway inhibits cell growth and induces apoptosis. NF-κB is known playing a vital role to control cell growth and apoptosis. Ginsenoside Rg3 is an herbal medicine with strong antitumor activity through inhibiting tumor growth and promoting tumor cell death. However, whether Rg3-induced inhibition on tumor development involves reduced NF-κB signaling and FUT4 expression remains unknown. In the present study, we found that Rg3 suppressed FUT4 expression by abrogating the binding of NF-κB to FUT4 promoter through inhibiting the expression of signaling molecules of NF-κB pathway, reducing NF-κB DNA binding activity and NF-κB transcription activity. NF-κB inhibitor (Bay 11-7082) or knocking down p65 expression by p65 siRNA also led to a significant decreased FUT4 expression. In addition, Rg3 induced apoptosis by activating both extrinsic and intrinsic apoptotic pathways. Moreover, in a xenograft mouse model, Rg3 downregulated FUT4 and NF-κB/p65 expression and suppressed melanoma cell growth and induced apoptosis without any noticeable toxicity. In conclusion, Rg3 induces tumor cell apoptosis correlated with its inhibitory effect on NF-κB signaling pathway-mediated FUT4 expression. Results suggest Rg3 might be a novel therapy agent for melanoma treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Binding Sites; Cell Line, Tumor; Cell Survival; Fucosyltransferases; Gene Expression Regulation, Neoplastic; Ginsenosides; Humans; Lewis X Antigen; Male; Melanoma; Mice; NF-kappa B; Promoter Regions, Genetic; Signal Transduction; Skin Neoplasms; Xenograft Model Antitumor Assays

An association between classical Hodgkin lymphoma (cHL) and mycosis fungoides (MF) or lymphomatoid papulosis has been reported in the literature. However, there can be considerable morphologic and immunophenotypic overlap between cHL and nodal involvement by CD30-positive T-cell lymphoproliferative disorders (CD30-T-LPD). To examine this potential association, biopsies from patients with a history of MF or primary cutaneous CD30-T-LPD and lymph node biopsies reported as either CD30-positive T-cell lymphoma (TCL) with Hodgkin-like cells or cHL were retrieved from the authors' institution. Of 11 cases identified, 10 were considered CD30-positive TCL with Hodgkin-like cells, whereas 1 was confirmed as cHL upon review. Five cases originally diagnosed as cHL were revised as CD30-positive TCL. Cases of CD30-positive TCL with Hodgkin-like cells showed a male predominance (M:F, 4:1) with a median age of 53 years (range, 44 to 72 y). Nearly all patients (9/10) initially presented with skin lesions. In 7/10 patients the draining lymph node was involved, whereas in 3 cases this could not be confirmed. Tumor cells morphologically resembled Hodgkin/Reed-Sternberg cells; they were uniformly strongly positive for CD30, and CD15 was expressed in 9/10 (90%) cases. A T-cell derivation was confirmed by T-cell antigen expression (7/10) and clonal rearrangement of T-cell receptor genes (9/10). In 3 cases a common T-cell clone was identified in skin and lymph node. B-cell markers (CD20/PAX5) were consistently negative. In 1 case the diagnosis of cHL followed by lymphomatoid papulosis was confirmed, with Hodgkin/Reed-Sternberg cells expressing PAX5, CD30, and CD15. In situ hybridization studies for Epstein Barr virus were negative. We show that cHL is less often associated with MF and primary cutaneous CD30-T-LPD than previously thought and that the coexpression of CD30 and CD15 in these TCLs may lead to a mistaken diagnosis of cHL.

Topics: Adult; Aged; Diagnosis, Differential; Female; Genetic Markers; Herpesvirus 4, Human; Hodgkin Disease; Humans; In Situ Hybridization; Ki-1 Antigen; Lewis X Antigen; Lymphatic Metastasis; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Male; Middle Aged; Mycosis Fungoides; Skin Neoplasms

Members of the family of carcinoembryonic antigen (CEA)-related cell adhesion molecules (CEACAMs) belonging to the immunoglobulin (Ig) superfamily are expressed in a variety of normal and malignant human tissues. As components of the cell membrane, these glycoproteins can make contact with adjacent cells. CEACAM1 and CEACAM5 (CEA) express Lewis(x) (Le(x)) structures. As shown by mass spectrometry in conjunction with enzymatic digestion, CEACAM1 contains at least seven Le(x) residues. Fucosyltransferase IX is the main fucosyltransferase responsible for attachment of terminal fucose, the key feature of the Le(x) structure, to CEA and CEACAM1. The Le(x) residues of both, CEACAM1 and CEA, interact with the human Le(x)-binding glycan receptors DC-SIGN and SRCL. Since subpopulations of human macrophages express DC-SIGN or SRCL, Le(x)-carrying CEACAMs may modulate the immune response in normal tissues such as the human placenta or in malignant tumours, for example in colorectal, pancreatic or lung carcinomas.

Topics: Antigens, CD; Carcinoembryonic Antigen; Cell Adhesion Molecules; Cell Line; Collectins; Colorectal Neoplasms; Female; Fucose; Fucosyltransferases; Humans; Intestinal Mucosa; Lectins, C-Type; Lewis X Antigen; Melanoma; Placenta; Polysaccharides; Pregnancy; Protein Binding; Receptors, Cell Surface; Receptors, Scavenger; Recombinant Proteins; Skin Neoplasms; Tissue Extracts

The glycoprotein counter-receptors for E-selectin borne on skin-homing T cells are poorly defined. In this study we have used flow cytometry to investigate the surface expression of potential carbohydrate ligands for E-selectin on HUT78, a skin-homing cutaneous T-cell lymphoma. These cells possessed high surface expression of the KM-93 epitope but not HECA 452 or CSLEX1 epitopes. The KM-93 antibody also blocked the binding of HUT78 cells to E-selectin. All these antibodies are reported to recognize sialyl Lewis X (sLex)-like molecules. Using an E-selectin affinity matrix, the main glycoprotein isolated from HUT78 cells was a molecular species of 90 000 MW. Other minor species of molecular weights 40 000, 60 000, 100 000, 120 000 and 200 000 were also identified as potential counter-receptors for E-selectin. Four of the purified counter-receptors (90 000, 100 000, 120 000 and 200 000 MW) stained positive with the KM-93 antibody. Immunoblot analysis of these purified glycoproteins established the identity of the 90 000 MW glycoprotein as l-selectin. Furthermore, an anti-l-selectin antibody inhibited the binding of HUT78 cells to E-selectin, probably by steric inhibition of the carbohydrate ligand for E-selectin that is borne on the C-type lectin domain of l-selectin. These results suggest that a carbohydrate epitope on l-selectin may act as a ligand for E-selectin on skin-homing T cells.

Topics: Antibodies, Monoclonal; E-Selectin; Epitopes; Flow Cytometry; Humans; Lewis Blood Group Antigens; Lewis X Antigen; Lymphoma, T-Cell, Cutaneous; Molecular Weight; Oligosaccharides; Receptors, Cell Surface; Sialyl Lewis X Antigen; Skin; Skin Neoplasms; Tumor Cells, Cultured

Mycosis fungoides (MF) and Sézary syndrome (SS) are closely related cutaneous T-cell lymphomas, which differ in several clinical aspects. We compared histological and immunophenotypical features of these two entities, which could be implicated in the dermotropism and epidermotropism, characteristic for both of them. Thirteen biopsy specimens from patients with established plaque-stage MF and 13 from SS patients were examined retrospectively, and 21 histological criteria were assessed. Further, 9 cryosections from MF lesions and 9 from SS lesions were stained for LFA, ICAM1, CD40, CD40-ligand, CD28, CD80, CTLA-4, CD86, FAS, FAS-ligand, CLA and CD15s. The only histological criteria that showed persistent differences were acanthosis (in 12 of 13 SS and in 7 of 13 MF specimens) and Pautrier collections (detected in 6 SS and 11 MF biopsies). Patterns of staining with the antibodies mentioned above were found to be similar. Our results indicate that these interaction molecules seem to be involved in the pathogenesis of MF and SS, but their immunohistochemical distribution does not contribute to the differentiation between the two entities.

Topics: Abatacept; Adult; Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, T-Lymphocyte; Antigens, Neoplasm; B7-1 Antigen; B7-2 Antigen; CD28 Antigens; CD40 Antigens; CD40 Ligand; CTLA-4 Antigen; Fas Ligand Protein; Female; Humans; Immunoconjugates; Immunohistochemistry; Intercellular Adhesion Molecule-1; Lewis X Antigen; Lymphocyte Function-Associated Antigen-1; Male; Membrane Glycoproteins; Middle Aged; Mycosis Fungoides; Sezary Syndrome; Skin; Skin Neoplasms

We report a 50-year-old man with a history of malignant pleural mesothelioma diagnosed 1 year previously and treated with pneumonectomy and radiotherapy who presented with an erythematous eruption on the left chest wall. A skin biopsy showed a proliferation of malignant epithelioid cells lining irregular clefts in the dermis. Some groups of cells were observed filling vascular lumina. Immunohistochemically, the tumor cells expressed cytokeratins (with antibodies AE1/AE3, MNF 116, and CAM 5.2), and epithelial membrane antigen (EMA), and were negative with Ulex europaeus (UE) and for carcinoembryonic antigen (CEA), CD34, CD15 (with LeuM1 antibody), and factor VIII-related antigen (FVIIIra). The histologic features and immunohistochemical profile were comparable to those observed in the primary pleural mesothelioma. This is the first reported case in which malignant mesothelioma metastatic to the skin presented as "inflammatory carcinoma." Although a very uncommon presentation, mesothelioma should be considered in the differential diagnosis of erythematous eruptions on the chest.

Topics: Adenocarcinoma; Antigens, CD34; Carcinoembryonic Antigen; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Lewis X Antigen; Male; Mesothelioma; Middle Aged; Mucin-1; Pleural Neoplasms; Skin Neoplasms; Thorax; von Willebrand Factor

Studies of skin involvement in Hodgkin's disease are infrequent in the literature. In particular, immunophenotypic analyses of specific cutaneous infiltrates have been performed in only a few cases. We analyzed the clinical, histological and immunohistochemical features of specific cutaneous manifestations of Hodgkin's disease comparing histologic and immunophenotypic aspects of skin lesions with those of the nodal counterpart. Seven patients with Hodgkin's disease of the lymph nodes and specific cutaneous lesions, where both nodal and skin biopsies were available for histologic and immunohistochemical analyses, were included in this study. Immunohistochemical stains were performed with a 3-step immunoperoxidase technique on routinely-fixed, paraffin-embedded tissue sections. All 7 patients had nodular sclerosis Hodgkin's disease of the lymph nodes. In the skin, clinical presentations included reddish-brown papules, plaques, nodules and ulcerated tumors. Histologic examination of cutaneous lesions showed features consistent with nodular sclerosis Hodgkin's disease in 6 cases and unclassifiable Hodgkin's disease in one. Reed-Sternberg cells and lacunar cells were present in 4 cases (57.1%). Immunohistochemical analysis of Hodgkin's and Reed-Sternberg cells revealed a constant positivity for CD30 (BerH2) and negativity for CD45 (LCA) in both the lymph nodes and the skin. Staining with CD15 (M1) revealed positivity in 7/7 nodal samples and 5/7 skin biopsies. Cytoplasmic expression of immunoglobulin light chains (both lambda and kappa) was observed in one cutaneous case. The accompanying infiltrate was mostly composed of T-lymphocytes admixed with variable numbers of monocytes/macrophages and eosinophils. Our results indicate that the histology of cutaneous specific manifestations of Hodgkin's disease correlates with that of the nodal counterpart in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Hodgkin Disease; Humans; Immunoenzyme Techniques; Immunophenotyping; Lewis X Antigen; Lymph Nodes; Proliferating Cell Nuclear Antigen; Reed-Sternberg Cells; Skin Neoplasms

We investigated immunohistochemically the localization of lysozyme and Leu M1 in normal skin, 76 cases of benign sweat gland tumors, 28 cases of malignant sweat gland tumors, 23 cases of extramammary Paget's disease, 7 cases of sebaceous carcinoma, 6 cases of malignant trichilemmoma, 10 cases of squamous cell carcinoma, and 10 cases of basal cell carcinoma and compared the results with those for gross cystic disease fluid protein (GCDFP)-15 to assess the sensitivity and specificity of our assay conditions for apocrine differentiation. Normal apocrine glands were stained with all three antibodies, while eccrine glands were positive only for GCDFP-15, and other portions of normal skin were not stained with any of the antibodies used. In neoplastic tissue thought to be from apocrine tumors, antibodies raised against lysozyme and GCDFP-15 had a greater specificity (100%) for apocrine differentiation, while Leu M1 had a greater sensitivity (88%). Tissues that were stained with two or three of these antibodies appeared to exhibit apocrine differentiation. In the tumors examined, the specificity for apocrine differentiation was 100% and the sensitivity for such differentiation was 92% by these criteria. According to these criteria, some cases of syringocystadenoma papilliferum, primary mucinous carcinoma of the skin, and extramammary Paget's disease with underlying adenocarcinoma showed apocrine differentiation.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Sebaceous; Adenoma, Sweat Gland; Adolescent; Adult; Aged; Apocrine Glands; Apolipoproteins; Apolipoproteins D; Biomarkers, Tumor; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carrier Proteins; Cell Differentiation; Eccrine Glands; Female; Glycoproteins; Humans; Immunohistochemistry; Lewis X Antigen; Male; Membrane Transport Proteins; Muramidase; Neoplasm Proteins; Neoplasms, Basal Cell; Paget Disease, Extramammary; Sensitivity and Specificity; Skin; Skin Neoplasms; Sweat Gland Neoplasms

Expression of a variant type of sialyl Le(x) antigen defined by 2F3 monoclonal antibody on leukemia cells was studied in 15 adult T cell leukemia (ATL) patients. The expression of 2F3-defined sialyl Le(x) antigen on CD4+CD45+ cells, which is an ATL cell-rich population, was higher in patients with skin involvement (50.1 +/- 23.1% were positive) than in patients without skin involvement (18.1 +/- 12.5%) (P < 0.01). The other surface markers including classical sialyl Le(x) antigen defined by SNH3 or FH6 and LFA-1, VLA-4, CD4, CD25, ICAM-1, Leu8, and HLA-DR did not show a significant difference regardless of skin involvement. In the skin lesion of four patients that we could examine, infiltrating leukemia cells strongly expressed 2F3-defined sialyl Le(x) antigen. In one patient, we could also examine the expression of classical sialyl Le(x) antigen defined by SNH-3 and CSLEX-1, but this was almost negligible. Both skin and lymph node biopsy specimens were examined in two patients. Leukemia cells in the skin strongly expressed 2F3-defined sialyl Le(x) antigen, while its expression was almost negligible on the leukemia cells in the lymph node. These findings suggest that the expression of 2F3-defined sialyl Le(x) antigen on ATL cells is associated with skin involvement of ATL.

Topics: Adult; Aged; Aged, 80 and over; Cell Adhesion Molecules; Female; Humans; Leukemia, T-Cell; Lewis X Antigen; Male; Middle Aged; Skin Neoplasms

The results of several investigations proved that, in special circumstances, human keratinocytes (HKs) synthesize and express cell surface moieties characteristic of effector and/or accessory cells of the immune system, such as CD16, CD36, HLA-DR, and intercellular adhesion molecule-1 (CD54), which are all detectable on the surfaces of macrophages. In the present study, skin biopsies from healthy volunteers, from positive tuberculin skin tests, and from patients with acute urticaria (AU), lichen planus (LP), psoriasis vulgaris (PV), mycosis fungoides (MF), and purpura pigmentosa chronica (PPC) were investigated by means of a multistep immunoperoxidase method to examine the reactivity of the HKs with a panel of monoclonal antibodies (MABs) characteristic of monocyte/macrophage cell lines. In biopsies obtained from positive tuberculin tests and from clinically involved skin of patients with LP, PV, MF, or PPC, a multifocal, positive peroxidase reaction was observed on the membranes of HKs of the basal and suprabasal cell layers when the MABs OKM13 (CD13), OKM14 (CD14), and Dako-Macrophage (CD68) were used. In contrast, specific staining of the HKs was not observed with the same antibodies in the biopsies of healthy volunteers or of patients with AU or in the uninvolved skin specimens obtained from the other patients. The HKs of PV, LP, MF, PPC, and AU patients and those of the healthy subjects all failed to give positive reactions when MABs against CD11b, CD15, or CD33 were used. The published data supplement the known surface characteristics of HKs, reflecting their stage of activation and differentiation.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Surface; Biomarkers, Tumor; CD13 Antigens; Humans; Immunohistochemistry; Keratinocytes; Lewis X Antigen; Lichen Planus; Lipopolysaccharide Receptors; Macrophage-1 Antigen; Membrane Glycoproteins; Monocytes; Mycosis Fungoides; Psoriasis; Purpura; Sialic Acid Binding Ig-like Lectin 3; Skin; Skin Diseases; Skin Neoplasms; Tuberculosis, Cutaneous; Urticaria

Since its initial description, microcystic adnexal carcinoma (MAC) of the skin has been controversial. In particular, it features keratin production of the type seen in some pilar neoplasms , and has been thought to pursue partial follicular differentiation. Diagnostically, MAC may be difficult to separate from desmoplastic trichoepithelioma (DTE) in superficial biopsy specimens. We studied 12 MACs, 22 malignant eccrine acrospiromas, 7 sudoriferous syringometaplasias, 6 syringomas, 5 DTEs, and 40 other benign pilar neoplasms immunohistochemically. Paraffin sections and antibodies to "hard" (pilar) keratins. epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), Leu-M1, and S100 protein were employed. The MACs exhibited reactivity for hard keratin subclasses AE 13 and AE 14, EMA, CEA, and Leu-M1. Desmoplastic trichoepitheliomas expressed positivity for AE 14, EMA, and Leu-M1 focally, but lacked the other specified markers. Syringomas and malignant acrospiromas displayed EMA, CEA, and AE 14 reactivity, and 5 syringometaplastic lesions were AE 14-reactive. Benign pilar tumors aside from DTEs were reactive only for AE 13, AE 14, or both. These data indicate that MAC exhibits an immunophenotype that is a "hybrid" of those seen in pure sweat glandular and follicular neoplasms, and suggest that it may indeed show combined pilar and sudoriferous differentiation. Based on these results, it also appears that immunohistochemical analysis may be useful in the diagnostic separation of MAC and DTE.

Topics: Adenoma, Sweat Gland; Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma; Female; Humans; Immunohistochemistry; Keratins; Lewis X Antigen; Male; Membrane Glycoproteins; Middle Aged; Mitosis; Mucin-1; Skin; Skin Neoplasms